The observation of spontaneous clinical remissions, correlation of gene expression signatures of infiltrating nonmalignant immune cells in the tumor with survival, and the high response rates following administration of rituximab, an anti-CD20 monoclonal antibody suggest that follicular lymphomas are particularly immune responsive. However, immunosuppressive factors in the tumor microenvironment may render the endogenous anti-tumor immune responses ineffective. Recently, the inhibitory receptor programmed death 1 (PD-1), a negative regulator of activated T cells and natural killer cells, was demonstrated to be markedly upregulated on intratumoral CD4+ and CD8+ T cells in patients with follicular lymphoma. PD-1 expression was associated with impaired function of CD4+ and CD8+ T cells and blockade of the PD-1/PD-ligand pathway with antibody against PD-1 significantly enhanced proliferation of intratumoral CD4+ and CD8+ T-cells and induced production of TH1 but not TH2 cytokines in response to autologous tumor cells obtained from patients with follicular lymphoma. In the current proposal, we intend to reverse the inhibitory effects of the PD-1/PD-ligand pathway in patients with follicular lymphoma. The central hypothesis of this proposal is that blockade of the interaction of PD-1 with its ligands by using CT-011, an anti-PD-1 blocking antibody, will enhance the endogenous antitumor T-cell and natural killer-cell immune responses in patients with follicular lymphoma and lead to clinical regression of the tumors. Furthermore, we hypothesize that CT-011 will enhance the antibody-dependent cell-mediated cytotoxicity mediated by natural killer cells and lead to increased clinical efficacy following administration of rituximab. To accomplish the objectives of this proposal, we will conduct a phase 2 clinical trial of CT-011 combined with rituximab in patients with relapsed follicular lymphoma. Three Specific Aims are proposed: 1) determine the safety and clinical efficacy of CT-011 administered in combination with rituximab in patients with relapsed follicular lymphoma, 2) determine the effects of CT-011 on the frequency and function of tumor-specific T cells in patients with follicular lymphoma, and 3) determine the effects of CT-011 on the function of natural killer cells in patients with follicular lymphoma. The combination of the two drugs, CT-011 and rituximab is expected to improve the clinical efficacy without increasing the toxicity. Given that the median age of FL patients at diagnosis is 60 years, developing such nontoxic but efficacious immunotherapeutic approaches is highly desirable. PUBLIC HEALTH RELEVANCE: The combined use of the two antibody therapies, CT-011 and rituximab is likely to be complementary and may be even synergistic and lead to enhanced clinical efficacy without increasing the toxicity in patients with follicular lymphoma. Development of such efficacious but nontoxic immunotherapeutic approaches is highly desirable for the treatment of follicular lymphoma since it is most commonly diagnosed in the elderly population. Due to activation of multiple arms of the immune system using this approach, it can potentially minimize the emergence of tumor variants that escape the immune system and therefore can improve the chance of our goal to find a curative therapy for this disease.